Acute myeloid leukemia

Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia

Abstract

Acute myeloid leukemias (AML) are characterized by mutations of tumor suppressor and oncogenes, involving distinct genes in adults and children. While certain mutations have been associated with the increased risk of AML relapse, the genomic landscape of primary chemotherapy-resistant AML is not well defined. As part of the TARGET initiative, we performed whole-genome DNA and transcriptome RNA and miRNA sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified at least three genetic groups of patients with induction failure, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of apparent NUP98 mutations, and additional recurrent variants including those in KMT2C and MLLT10. Comparison of specimens before and after chemotherapy revealed distinct and invariant gene expression programs. While exhibiting overt therapy resistance, these leukemias nonetheless showed diverse forms of clonal evolution upon chemotherapy exposure. This included selection for mutant alleles of FRMD8, DHX32, PIK3R1, SHANK3, MKLN1, as well as persistence of WT1 and TP53 mutant clones, and elimination of FLT3, PTPN11, and NRAS mutant clones. These findings delineate genetic mechanisms of primary chemotherapy resistance in pediatric AML, which should inform improved approaches for its diagnosis and therapy.

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Acknowledgements

This paper is dedicated to the memory of Dr. Robert Arceci. This work was supported by the NCI U10 CA98543 (TARGET), U24 CA114766 (COG), U10 CA180886, U10 CA098413, U10 CA180899, P30 CA008748, R01 CA204396, by the Damon Runyon-Richard Lumsden Foundation Clinical Investigator and St. Baldrick’s Foundation Arceci Innovation Awards (to AK), and the Charles E. Trobman Scholarship (to NM). We thank T. Davidsen and P. Gesuwan for their support of the TARGET Data Coordinating Center and Alejandro Gutierrez, Gila Spitzer, and Maria Luisa Sulis for comments on the manuscript.

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Correspondence to Soheil Meshinchi or Alex Kentsis.

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AK is a consultant for Novartis. The other authors declare that they have no conflict of interest.

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McNeer, N.A., Philip, J., Geiger, H. et al. Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia. Leukemia 33, 1934–1943 (2019). https://doi.org/10.1038/s41375-019-0402-3

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